Our current investigations center on the effects of selected androgenic (dehydroepiandrosterone - DHEA), estrogenic (phytoestrogens) or other dietary supplements and/or botanical agents on neoplastic prostate stromal and epithelial cell growth, gene expression, and biochemical function, including cell-cell signaling. As a precursor to both estrogen and testosterone, DHEA excess may pose a potential cancer risk in hormone responsive tissues such as the prostate. We compared the effects of DHEA with those of T, DHT, and E2 on cell proliferation, and protein and/or gene expression of androgen receptor (AR), PSA, IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF binding proteins ?2,3, and 5 (IGFBPs-2-5), and estrogen receptor-beta (ER-B) in human LNCaP prostate cancer cells, which contain a functional, but mutated AR. Cell proliferation assays revealed significant stimulation by all four steroids. DHEA and E2- induced responses were similar, but delayed and reduced, compared with those of T and DHT. All four hormones increased gene and/or protein expression of PSA, IGF-IR, IGF-I, and IGFBP-2, and decreased those of AR, ER-beta, IGF-II, and IGFBP-3. There were no significant effects of hormone treatment on IGFBP-5 mRNA. DHEA and E2 responses were similar, and distinct from those of DHT and T, in time and dose dependent studies. To assess the extent to which these findings in LNCaP cells may be related to the mutant AR present in these cells, we are also comparing the effects of DHEA vs DHT, T, and E2 in prostate cancer cells at different stages of neoplastic development, and with varying AR status. In addition, we are evaluating the relative importance of the AR versus ER in modulating the effects of DHEA in prostate cancer epithelial cells, as well as the independent effects of androgens and estrogens on prostate stromal cell replication and function.